Genome-scale screens identify JNK-JUN signaling as a barrier for pluripotency exit and endoderm differentiation
Genome-scale screens identify JNK-JUN signaling as a barrier for pluripotency exit and endoderm differentiation
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基因组规模筛选发现 JNK-JUN 信号传导是多能性退出和内胚层分化的障碍
DOI：
10.1038/s41588-019-0408-9
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发表时间：
2019-06-01
期刊：
影响因子：
30.8
通讯作者：
Huangfu, Danwei
中科院分区：
文献类型：
--
作者：
Li, Qing V.;Dixon, Gary;Huangfu, Danwei
人类胚胎干细胞（ESC）和人类诱导多能干细胞为基于细胞的治疗和药物发现带来了巨大的希望。然而，同质分化仍然是一个重大挑战，突出了理解发育机制的必要性。我们进行了基因组规模的CRISPR筛选，以揭示定形内胚层（DE）分化的调节因子，这出乎意料地发现了五个Jun N末端激酶（JNK）-JUN家族基因作为DE分化的关键障碍。JNK-JUN通路不通过直接抑制DE增强子起作用。相反，JUN与OCT 4、NANOG、SMAD 2和SMAD 3共同占据ESC增强子，并通过阻止ESC增强子的退役和抑制SMAD 2和SMAD 3染色质结合从ESC到DE增强子的重新配置来特异性抑制退出多能状态。因此，JNK-JUN途径保护多能性免于早熟DE分化。JNK的直接药理学抑制显著提高了产生DE和DE衍生的胰腺和肺祖细胞的效率，突出了利用来自再生医学发育研究的知识的潜力。
Human embryonic stem cells (ESCs) and human induced pluripotent stem cells hold great promise for cell-based therapies and drug discovery. However, homogeneous differentiation remains a major challenge, highlighting the need for understanding developmental mechanisms. We performed genome-scale CRISPR screens to uncover regulators of definitive endoderm (DE) differentiation, which unexpectedly uncovered five Jun N-terminal kinase (JNK)-JUN family genes as key barriers of DE differentiation. The JNK-JUN pathway does not act through directly inhibiting the DE enhancers. Instead, JUN co-occupies ESC enhancers with OCT4, NANOG, SMAD2 and SMAD3, and specifically inhibits the exit from the pluripotent state by impeding the decommissioning of ESC enhancers and inhibiting the reconfiguration of SMAD2 and SMAD3 chromatin binding from ESC to DE enhancers. Therefore, the JNK-JUN pathway safeguards pluripotency from precocious DE differentiation. Direct pharmacological inhibition of JNK significantly improves the efficiencies of generating DE and DE-derived pancreatic and lung progenitor cells, highlighting the potential of harnessing the knowledge from developmental studies for regenerative medicine.